Intermediates for the hemisynthesis of taxanes and preparation processes therefor

ABSTRACT

The present invention relates to novel intermediates for the hemisynthesis of taxanes and to their processes of preparation. The compounds of the present invention include precursor compounds of taxane side chains.

[0001] The present invention relates to novel intermediates for thehemisynthesis of taxanes and to their processes of preparation.

[0002] Taxanes, natural substances with a diterpene skeleton which isgenerally esterified by a β-amino acid side chain derived from N-alkyl-or N-aroylphenylisoserine, are known as anticancer agents. Several dozentaxanes have been isolated from Taxaceae of the genus Taxus, such as,for example, paclitaxel (R₁=Ac, R₂=Ph, R₃=R₄=H), cephalomanine, theirderivatives deacetylated in the 10 position, or baccatins (derivativeswithout side chain) represented by the formulae 1 and 2 below.

[0003] To avoid rapidly exhausting its original source, Taxusbrevifolia, French researchers have sought to isolate paclitaxel fromrenewable parts (leaves) of T. baccata, the European yew. They have thusdemonstrated the probable biogenetic precursor of taxanes,10-deacetylbaccatin III, the springboard of choice for the hemisynthesisbecause of its relative abundance in leaf extracts.

[0004] The hemisynthesis of taxanes, such as paclitaxel or docetaxel(R₁=Ac, R₂=t-butyloxy, R₃=R₄=H), thus consists in esterifying the13-hydroxyl of a protected derivative of baccatin or of10-deacetylbaccatin III with a β-amino acid derivative.

[0005] Various processes for the hemisynthesis of paclitaxel or ofdocetaxel are described in the state of the art (EP-0 253 738, EP-0 336840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878,WO 94/07879, WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO94/14787). Two recent works, I. Georg, T. T. Chen, I. Ojima, and D. M.Vyas, “Taxane Anticancer Agents, Basic Science and Current Status”, ACSSymposium Series 583, Washington (1995) and Matthew Suffness, “Taxol®Science and Applications” CRC Press (1995), 1500 references cited,comprise exhaustive compilations of hemisyntheses of taxanes.

[0006] The β-amino acid side chains derived from N-alkyl- orN-aroylphenylisoserine of paclitaxel or docetaxel are of (2R,3S)configuration and one of the main difficulties in the hemisynthesis oftaxanes is to obtain an enantiomerically pure product. The first problemconsists in obtaining a pure enantiomer of the phenylisoserinederivatives employed in the hemisynthesis of taxanes. The second problemconsists in retaining this enantiomeric purity during the esterificationof the baccatin derivative and the subsequent treatments of the productsobtained including deprotection of the hydroxyls and similar treatments.

[0007] Many studies on asymmetric synthesis involving derivatives ofβ-amino acids have focused on the chemistry of isoserine and of itsderivatives, β-amino acids for which a dehydrated cyclic form is aβ-lactam (EP-0 525 589). The majority of the various syntheses ofphenylisoserine derivatives useful as precursors of taxane side chainsfocus on a common intermediate, (2R,3R)-cis-β-phenylglycidic acid, whichis subsequently converted to β-phenylisoserine by reaction with ammonia(EP-0 495 718) or a nucleophile (Gou et al., J. Org. Chem., 1983, 58,1287-89). These various processes require a large number of stages inorder to produce β-phenylisoserine of (2R,3S) configuration, necessarilywith a stage of racemic resolution by conventional selectivecrystallization techniques, either for cis-β-phenylglycidic acid or forβ-phenylisoserine, or subsequently, after conversion. Furthermore, inorder to retain the enantiomeric purity of taxane side chain precursorsduring the esterification of the baccatin derivative, various means havebeen provided, in particular by using cyclic intermediates of blockedconfiguration, which remove the risks of isomerization duringesterification reactions under severe reaction conditions. Inparticular, they involve β-lactam (EP-0 400 971), oxazolidine (WO92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO94/12482), oxazinone (EP-0 428 376) or oxazoline (WO 94/14787)derivatives. These cyclic precursors are prepared from the correspondingβ-phenylisoserine derivative. As for the latter, the processes providedinvolve a large number of stages and a necessary racemic resolution inorder to obtain the desired taxane side chain precursor. It was thusimportant to develop a novel route for the improved synthesis ofintermediates which are taxane side chain precursors, in particular ofenantiomers of cis-β-phenylglycidic acid, of β-phenylisoserine and oftheir cyclic derivatives.

[0008] Finally, for the hemisynthesis of taxanes and in particular ofpaclitaxel, the sole appropriate baccatin derivative used until now isthat for which the 7-hydroxy radical is protected by a trialkylsilyl(EP-0 336 840, WO 94/14787), the deprotection of which is carried outexclusively in acidic medium. It was thus also important to employ novelprotective groups for the hydroxyl functional group which in particularmake possible selective protection of the 7-hydroxy radical and inaddition allow a wider choice of operating conditions for thedeprotection stage.

[0009] The present invention relates first of all to an improved processfor the preparation of taxane side chain precursors.

[0010] The process according to the invention comprises converting acis-β-arylglycidate derivative of general formula I

[0011] in which

[0012] Ar represents an aryl, in particular phenyl, and

[0013] R represents a hydrocarbon radical, preferably a linear orbranched alkyl or a cycloalkyl optionally substituted by one or morealkyl groups,

[0014] wherein said process is carried out so as to regio- andstereospecifically introduce the β-N-alkylamide and the α-hydroxyl ortheir cyclic precursors in a single stage by a Ritter reaction.Depending on the reaction mixture, two types of Ritter reaction are thusdistinguished: one with opening of the oxetane, resulting in a linearform of the chain which is directly and completely functionalized, theother resulting in the direct formation of an oxazoline. The “*” symbolindicates the presence of an asymmetric carbon, with an R or Sconfiguration. In both cases, the Ritter reaction is stereospecific,with retention of C-2 configuration and inversion of C-3 configuration.The process according to the invention is advantageously carried out onone of the enantiomers of the cis-β-arylglycidate derivative of generalformula I, so as to obtain the corresponding enantiomer of the linearchain or of the oxazoline, without subsequently requiring a racemicresolution. According to the method of preparation of thecis-β-arylglycidate derivative of general formula I described below, Rrepresents an optically pure enantiomer of a highly sterically hinderedchiral hydrocarbon radical, advantageously a cycloalkyl substituted byone or more alkyl groups, in particular a cyclohexyl. R will thenpreferably be one of the enantiomers of the menthyl radical, inparticular (+) menthyl.

[0015] 1. Direct synthesis of the linear chain

[0016] The direct synthesis of the linear chain by the Ritter reactioncomprises reacting a cis-β-arylglycidate derivative of general formula Idefined above with a nitrile of formula

R₂—CN

[0017] in which

[0018] R₂ represents an aryl radical, preferably a phenyl,

[0019] in the presence of a proton acid, such as sulphuric acid,perchloric acid, tetrafluoroboric acid, and the like, and of water.

[0020] A β-arylisoserine derivative of general formula IIa

[0021] in which Ar, R and R₂ are defined above, is then obtained.

[0022] The reaction is carried out with inversion of the configurationof the C-3 of the cis-β-phenylglycidate derivative. Thus, starting froma (2R,3R)-cis-β-phenylglycidate derivative, the correspondingβ-arylisoserine derivative of (2R,3S) configuration is obtained.

[0023] The Ritter reaction is carried out in an appropriate solvent, ata temperature ranging from −75 to +25° C.

[0024] The appropriate solvent can be the nitrile itself, when it isliquid at the reaction temperature, or alternatively the acid itself(sulphuric, perchloric or tetrafluoroboric), or a solvent, such as, forexample, methylene chloride or ethyl ether. The proton acidsconventionally used can contain the water necessary for the hydrolysis.

[0025] When benzonitrile (R₂=phenyl) is employed with thecis-β-arylglycidate of general formula I of (2R,3R) configuration forwhich Ar represents a phenyl, then the corresponding β-arylisoserinederivative of general formula IIa of (2R,3S) configuration for which Arand R2 represent a phenyl is directly obtained, which product is noneother than the precursor of the side chain of paclitaxel.

[0026] 2. Direct synthesis of the cyclic chain

[0027] In this method, a Ritter reaction is also carried out with anitrile of formula

R′₂—CN

[0028] in which R′₂ represents R₂ defined above or a lower alkyl orlower perhaloalkyl radical, such as trichloromethyl, in the presence ofa Lewis acid, in particular the boron trifluoride acetic acid complex,boron trifluoride etherate, antimony pentachloride, tin tetrachloride,titanium tetrachloride, and the like, or of a proton acid, such as, forexample, tetrafluoroboric acid, the reaction being carried out inanhydrous medium.

[0029] As for the synthesis of the linear chain, the solvent can be thenitrile itself, when it is liquid at the reaction temperature, oralternatively an appropriate solvent, such as, for example, methylenechloride or ethyl ether. The reaction temperature also ranges from −75to +25° C.

[0030] In the absence of water, an intramolecular Ritter reaction iscarried out and the oxazoline of general formula IIb

[0031] in which Ar, R and R′₂ are as defined above, is obtained.

[0032] As in the Ritter reaction in the presence of water, the reactionis carried out with inversion of the configuration of the C-3 of thecis-β-phenylglycidate derivative. Thus, starting from a(2R,3R)-cis-β-phenylglycidate derivative, the corresponding oxazoline of(2R,3S) configuration is obtained.

[0033] For both Ritter reactions, in order to avoid the formation of afree carbocation which is the cause of many potential side reactions,the reactants are preferably added in the following order: i) thecomplex between the nitrile and the acid is first formed, then ii) theacid catalyst is added to the mixture composed of the oxirane and thenitrile.

[0034] The products obtained by this first stage, which areβ-arylisoserine derivatives of general formula IIa or oxazolinederivatives of general formula IIb, can be further converted in a secondoptional stage described hereinbelow or then converted to acids bycontrolled saponification, before being coupled to a protected baccatinderivative for the hemisynthesis of taxanes, in particular of paclitaxeland its 10-deacetylated derivatives or of docetaxel. In the case ofβ-arylisoserine derivatives of general formula IIa, the saponificationcan be preceded by a conventional stage of protection of the hydroxyl byan appropriate protective group. A derivative of general formula II′a

[0035] in which

[0036] Ar, R and R₂ are defined above, and

[0037] GP represents a protective group for the hydroxyl functionalgroup which is appropriate for the synthesis of taxanes, in particularchosen from alkoxy ether, aralkoxy ether, aryloxy ether orhaloalkoxycarbonyl radicals, such as, for example, methoxymethyl,1-ethoxyethyl, benzyloxymethyl or (β-trimethylsilylethoxy)methyl groups,tetrahydropyranyl or β-alkoxycarbonyl (TrOC) radicals, β-halogenated oralkylsilyl ethers or alkoxyacetyl, aryloxyacetyl, haloacetyl or formylradicals, is then obtained.

[0038] 3. Conversion of the derivatives of formula IIa or IIb

[0039] The derivatives of general formula IIa or IIb obtained above canoptionally be converted into novel intermediates which are side chainprecursors in the hemisynthesis of taxanes. These conversions take placewith retention of the configuration of the C-2 and C-3 positions. Thenovel intermediates obtained will thus have the same stereochemistry asthe derivatives of formula IIa or IIb from which they derive. Theproducts obtained in this second stage are subsequently converted intoacids by controlled saponification, before being coupled with aprotected baccatin derivative for the hemisynthesis of taxane, inparticular of paclitaxel or of docetaxel.

[0040] 3.1 Cyclization of the derivatives of general formula IIa

[0041] The derivatives of general formula IIa can subsequently beconverted into oxazolines of formula IIb according to conventionalmethods of the state of the art (WO 94/14787).

[0042] The β-arylisoserine derivatives of general formula IIa can alsobe converted into novel oxazolidinone cyclic intermediates of generalformula III′a

[0043] in which Ar and R are defined above and R″₂ represents R′₂defined above, an alkoxy radical, preferably a t-butoxy radical, or alinear or branched alkyl radical comprising at least one unsaturation,for example a 1-methyl-1-propylene radical, and the correspondingdialkyl acetals.

[0044] The oxazolidinones of general formula III′a are obtained first ofall by reacting a β-arylisoserine derivative of general formula IIa witha haloalkoxycarbonyl ester, in particular 2,2,2-trichloroethoxycarbonyl(TrOC), and then by cyclization in the presence of a strong organicbase, such as diazabicycloundecene (DBU). An oxazolidinone derivative ofgeneral formula IIIa

[0045] in which Ar and R are defined above, is then obtained.

[0046] The derivatives of general formula IIIa can also be obtained bydirect synthesis, by reacting the β-arylglycidate derivatives of formulaII′a with urea.

[0047] The acylated derivatives of general formula III′a are obtained byintroducing the R″₂—CO— radical according to the usual acylationtechniques, in the presence of an appropriate acylating agent, forexample an acyl halide of formula R″₂—CO—X, in which R″₂ is definedabove and X represents a halogen, or an anhydride of the correspondingacid.

[0048] The dialkyl acetals are obtained according to the usualtechniques for the formation of acetals.

[0049] 3.2 Opening of the oxazoline of general formula IIb

[0050] The β-arylisoserine derivative of general formula IIIb

[0051] in which Ar, R and R′₂ are defined above, is obtained byhydrolysis of the oxazoline of general formula IIb in acidic medium.

[0052] Advantageously, when R′₂ represents a lower perhaloalkyl, such astrichloromethyl, the R′₂—CO— radical constitutes a protective group forthe hydroxyl functional group.

[0053] This taxane side chain precursor can then be converted intoamides of general formula III′b

[0054] in which

[0055] Ar, R, R′₂ and R″₂ are defined above.

[0056] The precursor of the side chain of paclitaxel (R″₂=phenyl) or ofdocetaxel (R″₂=t-butoxy) can thus be obtained without distinction.

[0057] 4. Preparation of the cis-β-arylglycidic acid derivative offormula I

[0058] The cis-β-arylglycidic acid derivative of formula I can beprepared according to conventional processes of the state of the art orby simple esterification of cis-β-arylglycidic acid with thecorresponding alcohol R—OH. In order to improve the overall yield in thesynthesis of taxane chain precursors, a cis-β-arylglycidate derivativeof general formula I

[0059] in which

[0060] Ar is defined above and

[0061] R represents an optically pure enantiomer of a highly stericallyhindered chiral hydrocarbon radical,

[0062] is prepared in the process according to the invention by reactingthe aldehyde of formula

Ar—CHO

[0063] with the haloacetate of formula

X—CH₂—COOR

[0064] Ar and R being defined above and

[0065] X representing a halogen, in particular a chlorine or a bromine.

[0066] Advantageously, the optically pure enantiomer of a highlysterically hindered chiral hydrocarbon radical is a cycloalkylsubstituted by one or more alkyl groups, in particular a cyclohexyl.

[0067] The method involves a Darzens' reaction through which a mixtureof the two diastereoisomers, ester of (2R,3R)-cis-β-arylglycidic acidand (2S,3S)-cis-β-arylglycidic acid and of an optically pure enantiomerof the chiral alcohol R—OH, is obtained, since the Darzens' reaction,carried out with a highly sterically hindered haloacetate, resultsessentially in the cis form of the β-arylglycidate. Advantageously, thehighly sterically hindered chiral hydrocarbon radical will be chosen sothat it allows the physical separation of the two diastereoisomers fromthe reaction mixture, for example by selective crystallization, withoutrequiring a stereospecific separation of the desired enantiomer at theend of the reaction by conventional crystallization or chiral columnchromatography methods.

[0068] Advantageously, R—OH represents menthol, one of the rare highlysterically hindered chiral alcohols which is economic and commerciallyavailable in both its enantiomeric forms.

[0069] In the process for the synthesis of a precursor of the taxaneside chain, the goal is to prepare a cis-β-phenylglycidate of (2R,3R)configuration. In this case, the highly sterically hindered chiralhydrocarbon radical R will be selected so that the diastereoisomer ofthe cis-β-phenylglycidate of (2R,3R) configuration crystallizes firstfrom the reaction mixture. When R—OH is menthol, (+)-menthol isadvantageously employed.

[0070] The asymmetric Darzens' reaction is carried out in the presenceof a base, particularly an alkali metal alkoxide, such as potassiumtert-butoxide, or an amide, such as lithium bistrimethylsilylamide, inan appropriate solvent, in particular an ether, such as ethyl ether, ata temperature ranging from −78° C. to 25° C. The reaction results in adiastereoisomeric mixture composed virtually exclusively of thecis-glycidates, which can reach a yield of greater than 95%, in theregion of 97%. Treatment of the isolated product in an appropriatesolvent, in particular a methanol/water mixture, makes it possible toreadily obtain physical separation of the required diastereoisomers. Byfractional crystallization (2 stages), rapid enrichment in the desireddiastereoisomer is obtained, with a diastereoisomeric purity of greaterthan 99%.

[0071] The latter point is particularly important because it conditionsthe isomeric purity of the final taxane, the undesirablediastereoisomers exhibiting their own biological activity which isdifferent from that of the desired taxane.

[0072] It is remarkable to observe that the selective use of the twoenantiomers of the menthyl ester makes it possible to access, using thesame process, the 2 precursor diastereoisomers of the two enantiomers ofglycidic acid.

[0073] In addition to a fairly high yield of pure isolateddiastereoisomer (up to 45%), the diastereoisomeric purity of the majorproduct of the reaction, the ease of implementation of the reaction, thesimplicity and the speed of the purification, and the low cost of thereactants and catalysts make the industrial synthesis of this keyintermediate in the asymmetric synthesis of β-amino acids easy andeconomical to access.

[0074] When a derivative of general formula I obtained by an asymmetricDarzens' reaction is used in the process according to the invention, thederivatives of general formulae IIa, II′a, IIb, IIIa, IIIb and III′bdefined above are then obtained for which R represents an optically pureenantiomer of a highly sterically hindered chiral hydrocarbon radical,such as a cycloalkyl substituted by one or more alkyl groups, inparticular a cyclohexyl, preferably menthyl, advantageously (+)-menthyl.

[0075] The present invention also relates to these derivatives, whichare of use as intermediates in the synthesis of taxane side chains.

[0076] It should be noted that the present process constitutes a veryrapid access to the substituted chiral oxazolines already described inthe literature (WO 94/14787), in 3 stages from commercially availableproducts, instead of 6 to 8 stages.

[0077] 5. Controlled saponification

[0078] A controlled saponification of the derivatives of generalformulae IIa, II′a, IIb, IIIa, IIIb and III′b is carried out under mildconditions, so as to release the acidic functional group while retainingthe structure of the said derivatives, for example in the presence of analkali metal carbonate in a methanol/water mixture.

[0079] After controlled saponification, the derivatives of generalformulae IIa, II′a, IIb, IIIa, IIIb and III′b defined above in which Rrepresents a hydrogen atom are obtained, which derivatives can beemployed directly in the hemisynthesis of taxanes by coupling with anappropriate baccatin III derivative.

[0080] 6. Hemisynthesis of taxanes

[0081] 6.1 Esterification

[0082] The present invention thus also relates to a process for thehemisynthesis of taxanes of general formula IV,

C—B  (IV)

[0083] in which

[0084] C represents a side chain chosen from the radicals of followingformulae:

[0085] in which Ar, R₂, R′₂, R″₂, R₃ and GP are defined above, and

[0086] B represents a radical derived from baccatin III of generalformula V

[0087] in which

[0088] Ac represents the acetyl radical,

[0089] Bz represents the benzoyl radical,

[0090] Me represents the methyl radical,

[0091] R₄ represents an acetyl radical or a protective group for thehydroxyl functional group GP1, and

[0092] R₅ represents a protective group for the hydroxyl functionalgroup GP2, by esterification of an appropriate baccatin III derivativeof general formula V, carrying a C-13 hydroxyl functional group, withone of the derivatives of general formulae IIa, II′a, IIb, IIIa, III′a,IIIb and III′b defined above, in which R represents a hydrogen atom,under conventional conditions for the preparation of taxanes as definedin the state of the art (in particular: EP-0 253 738, EP-0 336 840, EP-0336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO94/07879, WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO94/14787).

[0093] The GP1 and GP2 protective groups are, independently of oneanother, conventional groups employed in the hemisynthesis of taxanes,such as trialkylsilyls (EP-0 336 840) or TrOC (EP-0 336 841).

[0094] GP1 and GP2 also represent, independently of one another, linearor branched hindered haloalkoxycarbonyl radicals comprising at least onehalogen atom. They are advantageously radicals in which the alkylresidue comprises between 1 and 4 carbon atoms and 3 or 4 halogen atoms,preferably chosen from 2,2,2-tribromoethoxycarbonyl,2,2,2,1-tetrachloroethoxycarbonyl, 2,2,2-trichloro-t-butoxycarbonic andtrichloromethoxycarbonyl radicals, radicals which are all more hinderedthan the haloalkoxycarbonyl (TrOC) used until now to protect taxanes inthe 7 position.

[0095] GP1 and GP2 also represent, independently of one another, acylradicals in which the carbon α to the carbonyl functional group carriesat least one oxygen atom.

[0096] These acyl radicals are described in particular in EP-0 445 021.They are advantageously alkoxy- or aryloxyacetyl radicals of formula

R₆—O—CH₂—CO—

[0097] in which R₆ represents a sterically hindered alkyl radical, acycloalkyl radical or an aryl radical, or arylidenedioxyacetyl radicalsof formula

[0098] in which Ar″ represents an arylidene radical.

[0099] Sterically hindered alkyl is preferably understood to mean alinear or branched C₁-C₆ alkyl radical substituted by one or more bulkysubstituents chosen from halogens or linear or branched C₁-C₆ alkyl,linear or branched C₁-C₆ alkoxy or C₃-C₆ cycloalkyl or aryl radicals. Itwill be, for example, a tert-butyl or triphenylmethyl radical.

[0100] Cycloalkyl is preferably understood to mean a C₃-C₆ cycloalkylradical optionally substituted by one or more bulky substituents chosenfrom halogens or linear or branched C₁-C₆ alkyl, linear or branchedC₁-C₆ alkoxy or aryl radicals. Advantageously, it is a cyclohexylradical substituted by one or more linear or branched C₁-C₆ alkylradicals, such as, for example, menthyl, its racemate or its enantiomersand their mixtures in all proportions.

[0101] Aryl is preferably understood to mean a phenyl, naphthyl, anthrylor phenantryl radical optionally substituted by one or more bulkysubstituents chosen from halogens or linear or branched C₁-C₆ alkyl,linear or branched C₁-C₆ alkoxy or aryl radicals, in particular thephenyl radical. It is preferably a phenyl radical optionally substitutedby one or two above bulky substituents ortho- and ortho′- to the etherbond.

[0102] Finally, arylidene is preferably understood to mean a phenylene,naphthylene, anthrylene or phenanthrylene radical optionally substitutedby one or more bulky substituents chosen from halogens or linear orbranched C₁-C₆ alkyl, linear or branched C₁-C₆ alkoxy or aryl radicals,in particular the phenyl radical.

[0103] GP1 and GP2 also represent, independently of one another, atrialkylgermanyl radical or together form a divalent radical of formula

—SiR₇—O—SiR₈—

[0104] in which

[0105] R₇ and R₈, independently of one another, represent a stericallyhindered alkyl radical as defined above; in particular, R₇ and R₈ eachrepresent an isopropyl radical.

[0106] 6.2 Optional opening

[0107] When C represents a radical of formula IIb or IIIa, the oxazolinering is opened in order to obtain a taxane derivative of formula VI

[0108] in which

[0109] Ac, Bz, Me, Ar, R′₂, R₄ and R₅ are defined above.

[0110] The IIb, IIIa and III′a radicals are generally opened byhydrolysis in acidic or basic medium. The radical of formula IIb can beopened according to the methods described in the state of the art (inparticular WO 94/14787), by hydrolysis in acidic medium, followed bytreatment in basic medium, in order to obtain the derivative of generalformula VI.

[0111] 6.3 Deprotection

[0112] Finally, the hydroxyls of the derivatives of general formula V orVI are deprotected by replacing the protective groups for the hydroxylfunctional group, GP (when C represents the II′a radical), GP1 (when R₄is other than an acetyl) and GP2, by a hydrogen atom according to theusual techniques.

[0113] For the derivatives of general formula V in which C represents aradical of formula IIb or IIIa and GP1 and/or GP2 are, independently ofone another, conventional groups employed in the hemisynthesis oftaxanes, such as trialkylsilyls, the deprotection is carried outsimultaneously with the opening described above.

[0114] When GP1 and/or GP2 are bulky haloalkoxycarbonyl radicals,deprotection is carried out according to the usual techniques describedfor TrOC, by the action of zinc or of zinc doped with heavy metals, suchas copper, in an organic solvent, in particular in acetic acid,tetrahydrofuran or ethyl alcohol, with or without water.

[0115] When GP1 and/or GP2 are acyl radicals in which the carbon α tothe carbonyl functional group carries at least one oxygen atom,deprotection is carried out in basic medium by saponification inmethanol at low temperature, advantageously with ammonia in methanol ata temperature of less than 10° C., preferably in the region of 0° C.

[0116] For the case where C represents a radical of formula IIb, openingof the oxazoline is carried out simultaneously with deprotection inbasic medium, in order to result, in one stage, in the correspondingtaxane derivative of general formula VI in which R₄ represents an acetylradical or a hydrogen atom and R₅ represents a hydrogen atom, incontrast to the opening in acidic medium described in the state of theart, which requires a second stage in basic medium.

[0117] The known protective groups are removed using known methods andthe oxazoline chain, when it was present, opened out by hydrolysis,giving taxanes in every respect identical to the reference taxanes. Byway of example, without, however, limiting the scope of the invention,paclitaxel, 10-deacetyltaxol, cephalomanine and docetaxel can beobtained from the corresponding protected derivatives.

[0118] The deblocking of the acyls in which the carbon α to the carbonylfunctional group carries at least one oxygen atom was first attemptedunder the conventional conditions regarded as the mildest, that is tosay zinc acetate in methanolic medium at reflux. In this case, as thereaction was complete in a few hours (compared to a few days foracetates), the C-7 epimer resulting from the conventionalretroaldolization equilibrium was always isolated, in addition to thedesired product. It being presumed that, even under the neutral, indeedslightly acidic, conditions, the main agents responsible were methanoland especially the temperature, we returned to the standard conditionsfor deblocking acyls described by early writers, by saponification inbasic medium in ethanol at low temperature. Under these conditions, nosignificant epimerization was observed. By way of example, we obtainedpaclitaxel, 10-deacetyltaxol, cephalomanine and docetaxel, in everyrespect identical to the reference taxanes, from the correspondingalkoxy- or aryloxyacetylated derivatives.

[0119] Finally, it should be noted that all the methods described above,which are nevertheless targeted at improving the overall yield of thehemisynthesis, consist in synthesizing the phenylisoserine chainbeforehand, for the purpose of converting it into one of the cyclicstructures mentioned above (β-lactams, oxazolidines or oxazolines).Thus, paradoxically, the apparent better performances in the coupling ofthese cyclic structures only compensates for the fall in overall yieldcaused by the addition of ring creation stages to the synthetic sequencefor the linear chain (i.e., a total of 9 stages). For the generalprocess for the synthesis of taxanes according to the invention, aproduct such as paclitaxel is obtained in only 5 stages:

[0120] (1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidate

[0121] (1S,2R,5S)-(+)-menthyl(4S,5R)-2,4-diphenyl-4,5-dihydroxazole-5-carboxylate

[0122] saponification

[0123] hemisynthesis (esterification)

[0124] opening and deprotection.

[0125] Finally, the present invention relates to the syntheticintermediates of general formulae IV, V and VI described above which areof use in the general synthesis of taxanes, a subject of the presentinvention.

[0126] Generally, hydroxycarbon radical is preferably understood tomean, according to the invention, a saturated or unsaturated hydrocarbonradical which can comprise one or more unsaturations, such as anoptionally unsaturated linear or branched alkyl, an optionallyunsaturated cycloalkyl, an aralkyl or an aryl, it being possible foreach optionally to be substituted by one or more substituents, inparticular alkyl substituents.

[0127] Linear or branched alkyl is preferably understood to mean,according to the invention, a C₁-C₆ alkyl, in particular chosen from themethyl radical, ethyl radical, propyl radical, isopropyl radical, butylradical and its various branched isomers, such as, for example,tert-butyl, pentyl radical and hexyl radical and their various branchedisomers. This definition also applies to the alkyl residues of thealkoxy or aralkoxy radicals.

[0128] Cycloalkyl is preferably understood to mean, according to theinvention, a C₃-C₆ cycloalkyl, in particular chosen from thecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radicals.

[0129] Aryl is preferably understood to mean, according to theinvention, an aromatic or heteroaromatic radical, in particular chosenfrom the phenyl, naphthyl, anthryl, phenantryl, pyridyl or pyrimidylradicals and the like.

[0130] Finally, halogen is preferably understood to mean chlorine,bromine or iodine. The haloalkoxycarbonyl radicals are preferablyradicals in which the alkyl residue comprises between 1 and 4 carbonatoms and 3 or 4 halogen atoms.

[0131] The general process for the synthesis of taxanes according to theinvention is repeated in Scheme 1 below, wherein R represents(+)-menthyl and R₂ or R′₂ represent phenyl.

[0132] The final stage in the hemisynthesis of taxanes by the processaccording to the invention is summarized in Schemes 2 and 3 below.Scheme 2 summarizes the synthesis of paclitaxel from derivatives offormula IV defined above in which C represents a radical of formulae IIbor III′a. Scheme 3 summarizes the synthesis of 10-deacetyltaxol from aderivative of formula IV in which C represents a radical of formula IIb.

[0133] Of course, the same synthetic schemes can be used for the otherdefinitions of the substituents.

EXAMPLES I. Taxane Side Chain Precursors Example 1(1S,2R,5S)-(+)-Menthyl chloroacetate

[0134]

[0135] 57 mL (0.704 mol) of anhydrous pyridine were added to a stirredsolution at room temperature of 100 g (0.640 mol) of(1S,2R,5S)-(+)-menthol in 1 L of dry dichloromethane. After stirring fora few minutes, 56 mL (0.704 mol) of chloroacetyl chloride weresubsequently added and the reaction was allowed to continue for 30 min.After monitoring by T.L.C., 50 g of crushed ice were added and thereaction mixture was left vigorously stirring for 1 h. After dilutingwith 100 mL of dichloromethane, the organic phase was washed severaltimes with a saturated aqueous sodium chloride solution (200 mL), driedover MgSO₄ and then concentrated under reduced pressure. After purifyingthe crude product thus obtained by silica gel chromatography (15-40 μm)(eluent: cyclohexane/ethyl acetate, 20/1), 146 g of(1S,2R,5S)-(+)-menthyl chloroacetate were obtained in the form of asyrup.

[0136] The compound obtained exhibited the following characteristics:

[0137] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 4.77 (1H, dt), 4.06 and 4.02 (2H,2d, J=13.6 Hz), 2.02 (1H, m, J=11.8 Hz), 1.87 (1H, m, J=7 and 2.6 Hz),1.69 (2H, m), 1.50 (1H, m), 1.43 (1H, m, J=11.7 and 3 Hz), 1.07 (1H. m),1.02 (1H, q, J=11.8 Hz), 0.92 and 0.90 (6H, 2d, J=6.4 Hz), 0.89 (1H, m),0.77 (3H, d, J=7 Hz).

Example 2 (1S,2R,5S)-(+)-Menthyl (2R,3R)-3-phenylglycidate

[0138]

[0139] 69 mL (0.686 mol) of benzaldehyde were added to a stirredsolution at room temperature of 152 g (0.653 mol) of(1S,2R,5S)-(+)-menthyl chloroacetate in 600 mL of anhydrous ethyl ether.After stirring for a few minutes, the solution was cooled to −78° C.under an inert atmosphere, a suspension of 85 g (0.718 mol) of potassiumtert-butoxide in 400 mL of anhydrous ethyl ether was subsequently addedover 2 h and the reaction mixture was allowed to return to roomtemperature. After monitoring by T.L.C., the organic part was dilutedwith 200 mL of dichloromethane, washed several times with a saturatedsodium chloride solution, dried over MgSO₄ and concentrated underreduced pressure. 200 g of a crude product were thus obtained in theform of a syrup containing four diastereoisomers (of which two were cisand two were trans), which was subjected as-is to a fractionalcrystallization.

[0140] In a first step, the solution of the crude product in 2 L ofmethanol was brought to 60° C., to which 700 mL of osmosed water weregradually added, and was left for 16 h at room temperature without beingsubjected to vibrations. A yellow-colored lower solid phase rich intrans isomers was discarded and the white crystals of the upper phase,which are rich in cis isomers, were separated by filtration. Thecrystals thus obtained were redissolved in 2 L of methanol brought to60° C., 500 mL of osmosed water were added, until a persistentcloudiness was obtained, and the mixture was left for 16 h at roomtemperature. Three additional crystallizations, carried out according tothe same process but with reduced volumes of methanol (1 L) and water(200 mL), were necessary to obtain 23 g of (1S,2R,5S)-(+)-menthyl(2R,3R)-3-phenylglycidate in the crystalline state with an HPLCpurity>99% (Yd=12%).

[0141] The compound obtained exhibited the following characteristics:

[0142] M.p.=104° C.

[0143] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.40 (2H, dd, J=7.8 Hz and 1.7Hz), 7.32 (3H, m), 4.58 (1H, dt, J=10.9 Hz and 4.2 Hz), 4.26 (1H, d,J=4.6 Hz), 3.83 (1H, d, J=4.8 Hz), 1.6 to 0.85 (9H, m), 0.78 (3H, d, J=7Hz), 0.75 (3H, d, J=6.4 Hz), 0.62 (3H, d, J=6.9 Hz).

[0144] X-ray diffraction of a (1S,2R,5S)-(+)-menthyl(2R,3R)-3-phenylglycidate single crystal for the purpose of the indirectdetermination of the absolute configuration:

[0145] The single crystal was obtained from a crystalline suspensionresulting from the addition, while hot, of the non-solvent (water) to asemi-saturated solution of the glycidate in methanol. On slow cooling,fine needles with a purity of 99.95% (HPLC) were deposited by thissolution, which needles were stored under moist conditions until thefinal selection.

[0146] The selected sample (fine needle with dimensions 0.12×0.12×0.40mm) was studied on a CAD4 Enraf-Nonius automatic diffractometer(molybdenum radiation with graphite monochromator). The unit-cellparameters were obtained by refinement of a set of 25 reflections with ahigh theta angle. Data collection (2θ_(max)=50°, scanning ω/2θ=1,t_(max)=60 s, HKL domain: H 0.6 K 0.14 L 0.28, intensity controlswithout significant drift (0.1%)) provided 1888 reflections, 1037 ofwhich with l>1.5σ(l). C₁₉H₂₆O₃: Mr=302.42, orthorhombic, P2₁2₁2₁,a=5.709(11), b=12.908(4), c=24.433(8) Å, V=1801(5) Å⁻³, Z=4, D_(z)=1.116Mg.m⁻³, λ(MoKα)=0.70926 Å, μ=0.69 cm⁻¹, F(000)=656, T=294 K, finalR=0.072 for 1037 observations.

[0147] After Lorenz corrections and polarization corrections, thestructure was solved using Direct Methods which made it possible tolocate the majority of the nonhydrogen atoms of the molecule, theremaining atoms being located by Fourier differences and successivescaling operations. After isotropic refinement (R=0.125) and thenanisotropic refinement (R=0.095), most of the hydrogen atoms werelocated using a Fourier difference (between 0.39 and 0.14 eÅ⁻³), theothers being positioned by calculation. The complete structure wasrefined by whole matrix (x, y, z, β_(ij) for C and O, x, y, z for H; 200variables and 1037 observations; w=1/σ(F₀)²=[σ²(l)+(0.04F₀ ²)²]^(−½))resulting in R=0.080, R_(W)=0.072 and S_(W)=1.521 (residue Δp≦0.21eÅ⁻³).

[0148] The scattering factors are taken from the International Tables ofcrystallography [International Tables for X-ray Crystallography (1974),Vol. IV, Birmingham: Kynoch Press (Current distributor D. Reidel,Dordrecht)]. The calculations were carried out on a Hewlett-Packard9000-710 for the determination of the structure [Sheldrick, G. M.(1985), Crystallographic Computing 3: Data Collection, StructureDetermination, Proteins and Databases, edited by G. M. Sheldrick, C.Krüger and R. Goddard, Oxford, Clarendron Press] and on a DigitalMicroVax 3100 for the other calculations with the MOLEN suite ofprograms [Fair, C. K. (1990), MOLEN: An Interactive Intelligent Systemfor Crystal Structure Analysis, Enraf-Nonius, Delft, The Netherlands].

ORTEP DIAGRAM

[0149] [Johnson, C. K. (1965), ORTEP, Report ORNL-3794, Oak RidgeNational Laboratory, Tennessee, USA]

[0150] A (1S,2R,5S)-(+)-menthyl (2R,3R)-3-phenylglycidate sample, bytreatment with sodium methoxide in methanol, made it possible to obtainthe corresponding methyl phenylglycidate, the characteristics of whichwere as follows:

[0151] [α]_(D) ²⁸=+12 (c=1.15, chloroform)

[0152] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.40 (2H, d, J=8 Hz), 7.32 (3H,m), 4.26 (1H, d, J=4.6 Hz), 3.84 (1H, d, J=4.6 Hz), 3.55 (3H, s).

Example 3 (1S,2R,5S)-(+)-Menthyl(4S,5R)-2,4-diphenyl4,5-dihydrooxazole-5-carboxylate

[0153]

[0154] 15 mL (0.109 mol) of a 54% solution of tetrafluoroboric acid inether were added over 10 min to a stirred solution, under an inertatmosphere at −65° C., of 30 g (0.0993 mol) of (1S,2R,5S)-(+)-menthyl(2R,3R)-3-phenylglycidate and 305 mL (2.98 mol) of benzonitrile in 1.5 Lof anhydrous dichloromethane. The reaction was allowed to continue at−65° C. for 1 h and, after monitoring by T.L.C., 300 mL of a saturatedaqueous sodium hydrogencarbonate solution were added and the reactionmixture was allowed to return to room temperature with stirring. Afterextracting the aqueous phase with dichloromethane (2×200 mL), thecombined organic phases were washed with a saturated sodium chloridesolution (200 mL) and with water (50 mL) and dried over MgSO₄. Afterconcentrating under reduced pressure and removing the residualbenzonitrile under high vacuum at 50° C., the crude product obtained waspurified by silica gel chromatography (15-40 μm) (eluent:cyclohexane/ethyl acetate, 20/1).

[0155] 32 g of (1S,2R,5R)-(+)-menthyl(4S,5R)-2,4-diphenyl4,5-dihydrooxazole-5-carboxylate were thus isolatedin the form of a colorless syrup (Yd=80%) which exhibited the followingcharacteristics:

[0156] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.1Hz), 7.54 (1H,t, J=7.4 Hz), 7.46 (2H, t, J=7.4 Hz), 7.34 (5H, m), 5.40 (1H, d, J=6.4Hz), 4.88 (1H, d, J=6.4 Hz), 4.85 (1H, dt, J=10.9 and 4.4 Hz), 2.09 (1H,m), 1.84 (1H, m, J=7 and 2.7 Hz), 1.71 (1H, m), 1.69 (1H, m), 0.94 (3H,d, J=6.5 Hz), 0.9 (1H, m), 0.85 (3H, d, J=7 Hz), 0.77 (3H, d, J=7 Hz).

Example 4 (4S,5R)-2,4-Diphenyl-4,5-dihydrooxazole-5-carboxylic acid

[0157]

[0158] 25 mL of a solution of 6 g (43.2 mmol) of potassium carbonate inosmosed water were added to a stirred solution at room temperature of3.5 g (8.64 mmol) of (1S,2R,5S )-(+)-menthyl(4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylate in methanol (70mL) and the reaction was left to continue for 16 h at room temperature.After monitoring by T.L.C., the reaction mixture was concentrated underreduced pressure. The aqueous phase thus obtained was washed withdichioromethane (3×100 mL), acidified to pH 2 by slow addition of 20 mLof a 1M aqueous HCl solution and extracted with ethyl acetate (3×100mL). The combined organic extraction phases were dried (MgSO₄) andconcentrated under reduced pressure.

[0159] 2.26 g of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylicacid were thus obtained in the form of a white powder (Yd=98%) whichexhibited the following characteristics:

[0160] [α]_(D) ²²=+27.7 (c=0.99, CH₂Cl₂/MeOH, 1/1)

[0161] F=201-202° C.

[0162] 400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 7.99 (2H, d, J=7.3 Hz), 7.64(1H, t, J=7.4 Hz), 7.55 (2H, t, J=7.7 Hz), 7.36 (5H, m), 5.40 (1H, d,J=6.3 Hz), 4.99 (1H, d, J=6.4 Hz).

Example 5 (1S,2R,5S)-(+)-Menthyl (2R,3S)-N-benzoyl-3-phenylisoserinate

[0163]

[0164] 15 mL of a 1M aqueous HCl solution were added to a stirredsolution at room temperature of 1 g (2.47 mmol) of(1S,2R,5S)-(+)-menthyl(4S,5R)-2,4-diphenyl4,5-dihydrooxazole-5-carboxylate in a mixture ofmethanol (15 mL) and tetrahydrofuran (15 mL). The reaction mixture wasbrought for 1 h to reflux and, after monitoring by T.L.C. and returningto room temperature, a saturated aqueous sodium hydrogencarbonatesolution (45 mL) was gradually added until a basic pH was obtained.After stirring for 48 h at room temperature, the aqueous phase obtainedafter concentrating under reduced pressure was extracted withdichloromethane (100 mL). The aqueous phase was washed with a saturatedsodium chloride solution (2×50 mL), dried over MgSO₄ and concentratedunder reduced pressure and the residue obtained was chromatographed onsilica gel (15-40 μm) (eluent: dichloromethanelmethanol, 95/05).

[0165] 0.835 g of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-3-phenylisoserinate was thus isolated in the form of awhite solid (Yd=80%) which exhibited the following characteristics:

[0166] 400 MHz ¹H NMR (CDCl3) (δ ppm): 7.77 (2H, d, J=7.2 Hz), 7.51 (1H,t, J=7.3 Hz), 7.45 (4H, m), 7.36 (2H, t, J=7.2 Hz), 7.29 (1H, t, J=7.2Hz), 7.04 (1H, d, J=9.2 Hz), 5.78 (1H, dd, J=9.2 and 2.1Hz), 4.79 (1H,dt, J=10.9 and 4.4 Hz), 4.63 (1H, broad s), 3.35 (1H, broad s), 1.81(2H, m), 1.67 (3H, m), 1.5 to 1.36 (2H, m), 1.09 to 0.91 (2H, m), 0.89(3H, d, J=6.9 Hz), 0.77 (3H, d, J=6.5 Hz), 0.74 (3H, d, J=6.9 Hz).

Example 6 (1S,2R,5S)-(+)-Menthyl(2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinate

[0167]

[0168] 0.255 g (2.08 mmol) of 4-dimethylaminopyridine was added to asolution of 0.8 g (1.89 mmol) of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-3-phenylisoserinate in 10 mL of anhydrousdichloromethane. After stirring for a few minutes at room temperature,477 μL (2.84 mmol) of triethylsilyl chloride were added over 5 min.After stirring for 1 h at room temperature and monitoring by T.L.C., thereaction mixture was diluted with 100 mL of dichloromethane. The organicphase was washed with a saturated aqueous sodium hydrogencarbonatesolution (2×20 mL) and with a saturated sodium chloride solution (50mL), dried over MgSO₄ and concentrated under reduced pressure. Afterpurifying the residue obtained by silica gel chromatography (15-40 μm)(eluent: cyclohexane/ethyl acetate, 10/1), 0.74 g of(1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinate was obtained inthe form of a colorless syrup (Yd=75%).

[0169] The compound obtained exhibited the following characteristics:

[0170] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.82 (2H, d, J=7 Hz), 7.52 (1H,t, J=7.4 Hz), 7.45 (2H, t, J=7 Hz), 7.37 (2H, d, J=7.2 Hz), 7.32 (2H, t,J=7.2 Hz), 7.26 (2H, m), 5.60 (1H, dd), 4.73 (1H, dt, J=11 and 4.3 Hz),1.88 to 1.67 (m), 1.44 (2H, m), 1.06 and 0.87 (m), 0.80 (m), 0.67 (3H,d, J=7 Hz), 0.62 to 0.34 (m).

Example 7 (2R,3S)-N-Benzoyl-O-triethylsilyl-3-phenylisoserine

[0171]

[0172] A solution of 0.644 g (4.655 mmol) of sodium carbonate in 10 mLof osmosed water was added to a stirred solution at room temperature of0.5 g (0.931 mmol) of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinate in 15 mL ofmethanol. After stirring for 16 h at room temperature and monitoring byT.L.C., the reaction mixture was concentrated under reduced pressure andthe residual aqueous phase was washed with dichloromethane (3×50 mL) andthen acidified to pH 2 by slow addition of a 1M aqueous HCl solution (10mL). The aqueous phase was extracted with ethyl acetate (3×50 mL) andthe combined organic phases were dried over MgSO₄ and concentrated underreduced pressure.

[0173] 0.320 g of (2R,3S)-N-benzoyl-O-triethylsilyl-3-phenylisoserinewas obtained in the form of a white powder (Yd=90%) which exhibited thefollowing characteristics:

[0174] 400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 8.46 (1H, d, J=9.3 Hz), 7.82(2H, d, J=7.1Hz), 7.54 (1H, t, J=7.2 Hz), 7.47 (4H, m), 7.32 (2H, t),7.36 (1H, t), 5.44 (1H, dd, J=9.2 and 5.5Hz), 4.64 (1H, d, J=5.6Hz),0.77 (9H, m), 0.45 (6H, m).

Example 8 (1S,2R,5S)-(+)-Menthyl (2R,3S)-N-benzoyl-O-(2,2,2-trichloroethoxy)carbonyl-3-phenylisoserinate

[0175]

[0176] 480 mg (3.96 mmol) of 4-dimethylaminopyridine were added to astirred solution at room temperature under an inert atmosphere of 1.38 g(3.3 mmol) of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-3-phenylisoserinate in 30 mL of anhydrousdichloromethane. After stirring for 10 min, 540 μL (3.96 mmol) of2,2,2-trichloroethoxycarbonyl chloride were added over 5 min. Afterstirring for 2 h at room temperature and monitoring by T.L.C., theorganic phase was washed with a saturated sodium hydrogencarbonatesolution (2×10 mL) and with a saturated sodium chloride solution (10mL), dried over MgSO₄ and concentrated under reduced pressure. Afterpurifying the residue obtained by silica gel chromatography (15-40 μm)(eluent: cyclohexane/ethyl acetate, 5/1), 1.60 g of(1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-(2,2,2-trichloroethoxy)carbonyl-3-phenylisoserinatewere obtained in the form of a colorless syrup (Yd=82%).

[0177] The compound obtained exhibited the following characteristics:

[0178] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.82 (2H, d, J=7.4 Hz), 7.53 (1H,t, J=7.4 Hz), 7.44 (4H, m), 7.35 (2H, t, J=7 Hz), 7.29 (1H, t, J=7 Hz),7.09 (1H, d, J=9.3 Hz), 6.0 (1H, dd, J=9.3 and 2.5 Hz), 5.45 (1H, d,J=2.6 Hz), 4.78 and 4.72 (2H, 2d, J=11.9 Hz), 4.77 (1H, m), 1.85 (1H,m), 1.79 (1H, m), 1.65 (2H, m), 1.43 (1H, m), 1.02 (1H, m), 0.96 (1H,m), 0.86 (1H, m), 0.83 (3H, d, J=7 Hz), 0.78 (3H, d, J=6.5 Hz), 0.68(3H, d, J=6.9 Hz).

Example 9 (1S,2R,5S)-(+)-Menthyl(4S,5R)-4-phenyloxazolidin-2-one-5-carboxylate

[0179]

[0180] 1 mL (7.28 mmol) of 1,8-diazabicylo[5,4,0]undec-7-ene was addedto a stirred solution at room temperature under an inert atmosphere of3.96 g (6.62 mmol) of (1S,2R,5S)-(+)-menthyl(2R,3S)-N-benzoyl-O-(2,2,2-trichloroethoxy)carbonyl-3-phenylisoserinatein 30 mL of anhydrous dichloromethane. After stirring for 30 min at roomtemperature, the organic phase was washed with 10 mL of a saturatedsodium chloride solution, dried over MgSO₄ and concentrated underreduced pressure. After purifying the residue by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 7/3), 2.18g of the compound cited in the title were obtained in the form of ayellow syrup (Yd=95%).

[0181] The compound obtained exhibited the following characteristics:

[0182] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.40 (5H, m), 6.09 (1H, s), 4.93(1H, d, J=5.3 Hz), 4.86 (1H, dt, J=11 and 4.4 Hz), 4.73 (1H, d, J=5.4Hz), 2.05 (1H, m), 1.81 (1H, m), 1.71 (2H, m), 1.54 to 1.41 (3H, m),1.07 (2H, m), 0.94 (3H, d, J=6.5 Hz), 0.88 (3H, d, J=7 Hz), 0.77 (3H, d,J=7 Hz).

Example 10 (1S,2R,5S)-(+)-Menthyl(4S,5R)-N-t-butoxycarbonic-4-phenyloxazolidin-2-one-5-carboxylate

[0183]

[0184] 3.8 mL (6.07 mmol) of a 1.6M solution of n-butyllithium in hexanewere added to a stirred solution at −40° C. under an inert atmosphere of1.91 g (5.52 mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-4-phenyloxazolidin-3-one-5-carboxylate in 20 mL of anhydroustetrahydrofuran. After stirring for 10 min at 40° C., a solution of 1.81g (8.28 mmol) of t-butoxycarbonic anhydride in solution in 5 mL oftetrahydrofuran was added and the reaction mixture was allowed to returnto room temperature over 15 min. After diluting with 50 mL ofdichloromethane and washing with a 2% aqueous HCl solution until a pH=5is obtained, the organic phase was dried (MgSO₄) and concentrated underreduced pressure. After purifying the crude product by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 5/1), 2.12g of the compound cited in the title were obtained in the form of acolorless syrup (Yd=86%).

[0185] The compound thus obtained exhibited the followingcharacteristics:

[0186] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 7.45 to 7.26 (5H, m), 5.19 (1H,d, J=3.7 Hz), 4.86 (1H, dt, J=10.9 and 4.5 Hz), 4.66 (1H, d, J=3.7 Hz),2.05 (1H, m), 1.79 (1H, m), 1.73 (2H, m), 1.62 to 1.24 (3H, m), 1.33(9H, s), 1.11 (2H, m), 0.94 (3H, d, J=6.5 Hz) and (1H, m), 0.89 (3H, d,J=7 Hz), 0.77 (3H, d, J=7 Hz).

Example 11 (1S,2R,5S)-(+)-Menthyl(4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylate

[0187]

[0188] 0.25 mL (2.17 mmol) of benzoyl chloride was added to a stirredsolution at room temperature under an inert atmosphere of 500 mg (1.45mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-4-phenyloxazolidin-3-one-5-carboxylate and 176 mg (1.16 mmol) of4-pyrrolidinopyridine in 7 mL of anhydrous dichloromethane. Afterstirring for 3 h at 50° C., the reaction mixture was brought back toroom temperature and diluted with 20 mL of dichloromethane. The organicphase was washed with 10 mL of a saturated sodium chloride solution,dried over MgSO₄ and concentrated under reduced pressure. Afterpurifying the crude product by silica gel chromatography (15-40 μm)(eluent: cyclohexane/ethyl acetate, 5/1), 300 mg of the compound citedin the title were obtained in the form of a colorless syrup (Yd=46%).

[0189] The compound thus obtained exhibited the followingcharacteristics:

[0190] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.16 (2H, d, J=7.1Hz), 7.68 (1H,t), 7.53 (4H, m), 7.43 (3H, m), 5.57 (1H, d, J=4.4 Hz), 4.90 (1H, dt,J=10.9 and 4.4 Hz), 4.85 (1H, d, J=4.3 Hz), 2.07 (1H, m), 1.80 (1H, m),1.72 (2H, m), 1.47 (3H, m), 1.09 (2H, m), 0.95 (3H, d, J=6.5 Hz), 0.88(3H, d, J=7 Hz), 0.78 (3H, d, J=7 Hz).

Example 12 (4S,5R)-3-N-Benzoyl-4-phenyloxazolidin-3-one-5-carboxylicacid

[0191]

[0192] A solution of 75 mg (0.543 mmol) of potassium carbonate in 1 mLof water was added to a stirred mixture at room temperature of 120 mg(0.266 mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylate in 2 mL ofmethanol. After stirring for 30 min, the reaction mixture was dilutedwith 10 mL of water and the aqueous phase was washed with 5 mL ofdichloromethane. After acidifying to pH=4 by means of 1M HCl, theresidual aqueous phase was extracted with ethyl acetate (3×10 mL). Thecombined organic phases were washed with 5 mL of a saturated sodiumchloride solution, dried over MgSO₄ and concentrated under reducedpressure.

[0193] 40 mg of(4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acid wereobtained in the form of a white powder (Yd=52%) which exhibited thefollowing characteristics:

[0194] 400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 12.98 (1H, broad s), 7.95 (2H,d, J=7.1Hz), 7.63 (1H, t, J=7.4 Hz), 7.50 (2H, t, J=7.5 Hz), 7.42 (2H,m), 7.37 (3H, m), 4.90 (1H, d, J=5 Hz), 4.77 (1H, d, J=5 Hz).

Example 13 (4S,5R)-4-Phenyloxazolidin-3-one-5-arboxylic acid

[0195]

[0196] 10 mL of a homogeneous solution of 360 mg (8.67 mmol) of NaOH, 3mL of methanol and 0.5 mL of water in pyridine were rapidly added to astirred solution at 0° C. under an inert atmosphere of 300 mg (0.867mmol) of (1S,2R,5S)-(+)-menthyl(4S,5R)-4-phenyloxazolidin-2-one-5-carboxylate, 3 mL of methanol andthen 0.5 mL of water in 6.5 mL of pyridine. After stirring for 20 min at0° C., the reaction mixture was diluted with water (30 mL) and washedwith dichoromethane (30 mL). After acidifying to a pH=1, the residualaqueous phase was extracted with ethyl acetate (3×20 mL) and thecombined organic phases were dried (MgSO₄) and concentrated underreduced pressure.

[0197] 86 mg of (4S,5R)-4-phenyloxazolidin-3-one-5-carboxylic acid werethus obtained in the form of a yellow syrup (Yd=53%) which exhibited thefollowing characteristics:

[0198] 400 MHz ¹H NMR (d₆-DMSO) (δ ppm): 13.33 (1H, broad s), 8.46 (1H,s), 7.38 (5H, m), 4.89 (1H, d, J=5 Hz), 4.75 (1H, d, J=5 Hz).

II. Baccatin III Derivatives Example 147-O-Triethylsilyl-10-deacetylbaccatin III

[0199]

[0200] 6.2 mL (36.6 mmol) of triethylsilyl chloride were added over 10min to a stirred solution, at room temperature and under an inertatmosphere, of 10 g (18.3 mmol) of 10-deacetylbaccatin III and 8.17 g(54.9 mmol) of 4-pyrrolidinopyridine in 500 mL of anhydrousdichloromethane. After reacting for 3 h at room temperature, 10 g ofcrushed ice were added and the mixture was left stirring vigorously for10 min. The residual organic phase was washed with water (200 mL), driedover MgSO₄ and concentrated under reduced pressure.

[0201] After treating the crude product obtained with the minimum amountof ethyl acetate, 11.2 g of 7-O-triethylsilyl-10-deacetylbaccatin IIIwere obtained in the crystalline state (Yd=92.3%).

[0202] The product thus obtained exhibited the followingcharacteristics:

[0203] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.4 Hz), 7.60 (1H,t, J=7.5 Hz), 7.47 (2H, t, J=7.6 Hz), 5.60 (1H, d, J=7 Hz), 5.17 (1H, d,J=1.9 Hz), 4.96 (1H, d, J=8 Hz), 4.86 (1H, m), 4.41 (1H, dd, J=10.6 and6.6 Hz), 4.31 and 4.16 (2H, 2d, J=8.4 Hz), 4.26 (1H, d, J=1.9 Hz), 3.95(1H, d, J=6.9 Hz), 2.48 (1H, ddd, J=14.5, 9.7 and 6.7 Hz), 2.29 (3H, s),2.27 (2H, m), 2.08 (3H, s), 1.90 (1H, m), 1.73 (3H, s), 1.62 (1H, s),1.08 (6H, s), 0.94 (9H, t, J=8 Hz), 0.56 (6H, m).

Example 15 7-O-Triethylgermanyl-10-deacetylbaccatin III

[0204]

[0205] 80 μL (0.476 mmol) of triethylgermanyl chloride were added over10 min to a stirred solution, at room temperature and under an inertatmosphere, of 100 mg (0.183 mmol) of 10-deacetylbaccatin III and 41 mg(0.275 mmol) of 4-pyrrolidinopyridine in 4 ml of anhydrousdichloromethane and the mixture was stirred at 50° C. for 13 h. Aftercooling the reaction mixture and diluting with 15 mL of dichloromethane,1 g of crushed ice was added and the mixture was left stirringvigorously for 10 min. The residual organic phase was washed with asaturated sodium hydrogencarbonate solution (5 mL) and a saturatedsodium chloride solution (5 mL), dried over MgSO₄ and concentrated underreduced pressure. After chromatographing the crude product on silica gel(15-40 μm) (eluent: cyclohexane/ethyl acetate, 25/75), 67 mg of7-O-triethylgermanyl-10-deacetylbaccatin III were obtained in the formof a colourless syrup.

[0206] The product thus obtained exhibited the followingcharacteristics:

[0207] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.09 (2H, d, J=7.1Hz), 7.60 (1H,t, J=7.4 Hz), 7.48 (2H, t, J=7.6 Hz), 5.63 (1H, d, J=7.1Hz), 5.24 (1H,s), 4.99 (1H, d, J=8 Hz), 4.78 (1H, t), 4.32 (1H, d, J=8.3), 4.28 (1H,m), 4.17 (2H, m), 3.97 (1H, d, J=7 Hz), 2.59 (1H, m), 2.30 (3H, s), 2.24(1H, m), 2.10 (1IH, m), 2.03 (3H, s), 1.82 (1H, m), 1.73 (3H, s), 1.11(9H, m), 1.0 (6H, t, J=7.7 Hz).

Example 16 7-O-(2,2,2-Trichloro-t-butoxycarbonyl)-10-deacetylbaccatinIII

[0208]

[0209] 3.3 g (13.8 mmol) of 2,2,2-trichloro-t-butoxycarbonyl chloridewere added over 2 h to a stirred solution at 40° C. under an inertatmosphere of 5 g (9.19 mmol) of 10-deacetylbaccatin III and 1.1 mL ofanhydrous pyridine in 250 mL of dry dichloromethane. After reacting foran additional 30 min and returning to room temperature, the organicsolution was washed with a 2% aqueous HCl solution (30 mL), washed withosmosed water (2×100 mL), dried over MgSO₄ and concentrated underreduced pressure (Yd=55%). After chromatographing the crude product onsilica gel (15-40 μm) (eluent: cyclohexane/ethyl acetate, 60/40),7-O-(2,2,2-trichloro-t-butoxycarbonyl)-10-deacetylbaccatin III wasobtained in the form of a white powder.

[0210] The product obtained exhibited the following characteristics:

[0211] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7 Hz), 7.62 (1H,t, J=7.4 Hz), 7.49 (2H, t, J=7.6 Hz), 5.65 (1H, d, J=6.9 Hz), 5.44 (1H,dd, J=10.8 and 7.3 Hz), 5.39 (1H, d), 4.98 (1H, d, J=7.5 Hz), 4.89 (1H,m), 4.35 and 4.20 (2H, 2d, J=8.4 Hz), 4.10 (1H, d, J=7 Hz), 4.01 (1H, d,J=1.9Hz), 2.64 (1H, m), 2.31 (3H, s), 2.29 (1H, m), 2.11 (3H, d), 2.05(2H, m), 1.89 (3H, s), 1.09 (3H, s), 1.07 (3H, s).

Example 17 a) 7-O-Triethylsilylbaccatin III

[0212]

[0213] 0.54 mL (7.5 mmol) of acetyl chloride was added over 10 min to astirred solution at room temperature under an inert atmosphere of 1 g(1.5 mmol) of 7-O-triethylsilyl-10-deacetylbaccatin III and 1.25 mL (15mmol) of pyridine in 15 mL of dry dichloromethane. After reacting for 2h at room temperature and monitoring by T.L.C., 1 g of crushed ice wasadded and the mixture was left stirring vigorously for 10 min. Theresidual organic phase was washed with water (2×10 mL), dried over MgSO₄and concentrated under reduced pressure. After silica gel chromatography(15-40 μm) (eluent: cyclohexane/ethyl acetate, 60/40), 0.756 g of7-O-triethylsilylbaccatin III was obtained in the form of a white powder(Yd=70%).

[0214] The compound obtained exhibited the following characteristics:

[0215] 400 MHz ¹H NMR (CDCl3) (δ ppm): 8.11 (2H, d, J=7.1Hz), 7.6 (1H,t, J=7.4 Hz), 7.48 (2H, t, J=7.7 Hz), 6.46 (1H, s), 5.63 (1H, d, J=7Hz), 4.96 (1H, d, J=8.1Hz), 4.83 (1H, m), 4.49 (1H, dd, J=10.4 and 6.7Hz), 4.31 and 4.15 (2H, 2d, J=8.3 Hz), 3.88 (1H, d, J=7 Hz), 2.53 (1H,m), 2.29 (3H, s), 2.27 (2H, m), 2.19 (3H, d, J=0.8 Hz), 2.18 (3H, s),2.12 (1H, d), 1.88 (1H, m), 1.68 (3H, s), 1.65 (1tH, s), 1.2 (3H, s),1.04 (3H, s), 0.92 (9H, t), 0.59 (6H, m).

Example 18 7-O-(2,2,2-Trichloro-t-butoxycarbonyl)baccatin III

[0216]

[0217] 50 μL (0.695 mmol) of acetyl chloride were added to a stirredsolution at room temperature under an inert atmosphere of 260 mg of7-O-(2,2,2-trichloro-t-butoxycarbonyl-10-deacetylbaccatin III and 127.5mg (1.04 mmol) of 4-dimethylaminopyridine in 2.5 mL of drydichloromethane. After reacting for 1 h at room temperature, the organicphase was washed with a 2% aqueous HCl solution until a pH=6 isobtained, dried over MgSO₄ and concentrated under reduced pressure.After chromatographing the residue obtained on silica gel (15-40 μm)(eluent: cyclohexane/ethyl acetate, 6/4), 0.23 g of7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatin III was obtained in thesolid state (Yd=83%).

[0218] The compound obtained exhibited the following characteristics:

[0219] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.11 (2H, d, J=7.1Hz), 7.62 (1H,t, J=7.4 Hz), 7.49 (2H, t, J=7.6 Hz), 6.39 (1H, s), 5.64 (1H, d, J=6.9Hz), 5.61 (1H, dd, J=10.7 and 7.2 Hz), 4.99 (1H, d, J=8.2 Hz), 4.87 (1H,m), 4.33 and 4.16 (2H, 2d, J=8.4 Hz), 4.02 (1H, d, J=6.9 Hz), 2.64 (1H,ddd, J=14.4, 9.5 and 7.2 Hz), 2.30 (3H, s) and (2H, m), 2.17 (3H, s),2.13 (3H, d, J=0.8 Hz), 2.04 (1H, m), 1.83 (3H, s), 1.63 (1H, s), 1.14(3H, s), 1.09 (3H, s).

Example 19 7-O-Phenoxyacetyl-10-deacetylbaccatin III

[0220]

[0221] 1.05 mL (7.5 mmol) of phenoxyacetyl chloride were added over 10min to a stirred solution, at room temperature and under an inertatmosphere, of 1.03 g (1.88 mmol) of 10-deacetylbaccatin III and 0.6 mL(7.5 mmol) of anhydrous pyridine in 100 mL of dry dichloromethane. Afterreacting for 30 min at room temperature and monitoring by T.L.C., theorganic solution was washed with a 2% aqueous HC solution until a pH=2is obtained, washed with osmosed water (2×50 mL), dried over MgSO₄ andconcentrated under reduced pressure (Yd=70.5%). After chromatographingthe crude product on silica gel (15-40 μm) (eluent: cyclohexane/ethylacetate, 60/40), 7-O-phenoxyacetyl-10-deacetylbaccatin III was obtainedin the form of a white powder.

[0222] The product obtained exhibited the following characteristics:

[0223] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.09 (2H, d, J=7.3 Hz), 7.61 (1H,t, J=7.4 Hz), 7.48 (2H, t, J=7.6 Hz), 7.31 (2H, t, J=7.7 Hz), 6.99 (3H,m), 6.42 (1H, s), 5.61 (1H, d, J=7 Hz), 4.97 (1H, d, J=7.8 Hz), 4.86(3H, m), 4.44 (1H, dd, J=10.6 and 6.8 Hz), 4.30 and 4.15 (2H, 2d, J=8.4Hz), 3.86 (1H, d, J=7Hz), 2.56 (1H, m), 2.27 (3H, s), 2.27 (2H, m), 2.05((3H, s), 1.86 (1H, m), 1.68 (3H, s), 1.01 (3H, s), 0.98 (3H, s).

Example 20 7,10-O-Di(phenoxyacetyl)-10-deacetylbaccatin III

[0224]

[0225] 0.5 mL (3.68 mmol) of phenoxyacetyl chloride was added over 10min to a stirred solution, at room temperature and under an inertatmosphere, of 500 mg (0.92 mmol) of 10-deacetylbaccatin III and 0.6 mL(7.36 mmol) of anhydrous pyridine in 50 mL of dry dichloromethane. Afterreacting for 6 h at room temperature and monitoring by T.L.C., thesolution was washed with a 2% aqueous HCl solution until a pH=2 isobtained, washed with osmosed water (2×20 mL), dried over MgSO₄ andconcentrated under reduced pressure. After chromatographing the crudeproduct on silica gel (15-40 μm) (eluent: cyclohexane/ethyl acetate,6/4), 0.55 g of 7-1 0-O-bis(phenoxyacetyl)-10-deacetylbaccatin III wasobtained in the form of a white powder (Yd=74%).

[0226] The product obtained exhibited the following characteristics:

[0227] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.09 (2H, d, J=7.1Hz), 7.61 (1H,t, J=7.4 Hz), 7.48 (2H, t, J=7.6 Hz), 7.29 (2H, t, J=6.8 Hz), 7.22 (2H,t, J=7.5 Hz), 6.96 (4H, m), 6.84 (2H, d, J=7.9 Hz), 6.42 (1H, s), 5.69(1H, dd, J=10.5 and 7.1Hz), 5.60 (1H, d, J=6.9 Hz), 4.96 (1H, d, J=8.2Hz), 4.84 (1H, t, J=7.4 Hz), 4.8 (2H, s), 4.65 and 4.41 (2H, 2d,J=15.8Hz), 4.32 and 4.14 (2H, 2d, J=8.4 Hz), 3.98 (1H, d, J=6.8 Hz),2.65 (1H, m), 2.28 (3H, s), 2.26 (2H, m), 2.09 (3H, s), 1.80 (3H, s) and(1H, m), 0.98 (6H, s).

Example 21 7-O-Phenoxyacetylbaccatin III

[0228]

[0229] 0.233 mL (3.27 mmol) of acetyl chloride was added over 10 min toa stirred solution, at room temperature and under an inert atmosphere,of 1.11 g (1.64 mmol) of 7-O-phenoxyacetyl-10-deacetylbaccatin III in 40mL of anhydrous pyridine. After reacting for 16 h at room temperatureand monitoring by T.L.C., the reaction mixture was diluted with 50 mL ofosmosed water and the aqueous phase was extracted with ethyl acetate(3×30 mL). The combined organic phases were washed with water (2×20 mL),dried over MgSO₄ and concentrated under reduced pressure (Yd=84.5%).After silica gel chromatography (15-40 μm) (eluent: cyclohexane/ethylacetate, 60/40), 7-O-phenoxyacetylbaccatin III was obtained in thecrystalline state.

[0230] The product obtained exhibited the following characteristics:

[0231] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.1Hz), 7.61 (1H,t, J=7.4 Hz), 7.48 (2H, t, J=7.7 Hz), 7.27 (2H, t, J=8 Hz), 6.95 (3H,m), 6.26 (1H, s), 5.71 (1H, dd, J=10.4 and 7.2 Hz), 5.62 (1H, d, J=6.9Hz), 4.96 (1H, d, J=8.3 Hz), 4.80 (1H, m), 4.81 and 4.53 (2H, 2d, J=16Hz), 4.32 and 4.14 (2H, 2d, J=8.5 Hz), 4.0 (1H, d, J=6.9 Hz), 2.64 (1H,m), 2.29 (2H, m), 2.28 (3H, s), 2.24 (1H, d, J=5 Hz), 2.16 (3H, s), 2.09(3H, d, J=0.7 Hz), 1.81 (1H, m), 1.78 (3H, s), 1.13 (3H, s), 1.08 (3H,s).

Example 227-10-O-(1,1,3,3-Tetraisopropyl-1,3-disiloxanediyl)-10-deacetylbaccatinIII

[0232]

[0233] 1.28 ml (2.05 mmol) of n-butyllithium as a 1.6M solution inhexane were added over 10 min to a stirred solution, at −40° C. andunder an inert atmosphere, of 500 mg (0.93 mmol) of 10-deacetylbaccatinIII in 20 mL of anhydrous tetrahydrofuran. After stirring for 5 min, 350μL (1.12 mmol) of 1,3-dichloro-1,1,3,3-tetraisopropyidisyloxane wereadded and the reaction mixture was allowed to return to room temperatureover 20 min. After stirring for 1 h at room temperature, 225 mg (2.05mmol) of 4-dimethylaminopyridine were added and the reaction mixture wasleft stirring for an additional 1 h. After adding 20 mL of a saturatedaqueous sodium chloride solution, the mixture was extracted withdichloromethane (3×30 mL). The combined organic phases were washed witha saturated aqueous sodium chloride solution (20 ml), dried over MgSO₄and concentrated under reduced pressure. After purifying by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 60/40),480 mg of7,10-O-(1,1,3,3-tetraisopropyl-1,3-disyloxanediyl)-10-deacetylbaccatinIII were obtained in the amorphous state (Yd=65%).

[0234] The product obtained exhibited the following characteristics:

[0235] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.10 (2H, d, J=7.2 Hz), 7.60 (1H,t, J=7.4 Hz), 7.47 (2H, t, J=7.6 Hz), 5.60 (1H, s), 5.59 (1H, d), 4.97(1H, d, J=7.9 Hz), 4.87 (1H, m), 4.68 (1H, dd, J=10.4 and 6.9 Hz), 4.30and 4.17 (2H, 2d, J=8.5 Hz), 3.92 (1H, d, J=7.1Hz), 2.49 (1H, m), 2.28(3H, s), 2.27 (1H, m), 2.04 (1H, m), 1.91 (1H, m), 1.67 (3H, s), 1.55(1H, s), 1.32 to 0.85 (34H, m).

Example 2313-O-[[(4S,5R)-2,4-Diphenyl-4,5-dihydroxazol-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII

[0236]

[0237] 2.06 g (10 mmol) of dicyclohexylcarbodiimide were added to astirred solution, at room temperature and under an inert atmosphere, of2.67 g (10 mmol) of (4S,5R)-2,4-diphenyl-4,5-dihydroxazol-5-carboxylicacid in 55 mL of anhydrous toluene. After stirring for 5 min, 3.5 g (5mmol) of 7-O-triethylsilylbaccatin III and 0.61 g (5 mmol) of4-dimethylaminopyridine were added and the reaction mixture was broughtto 70° C. for 1 h. After returning to room temperature and removing theinsoluble materials by filtration, the organic phase was concentratedunder reduced pressure. After purifying the crude product by silica gelchromatography (15-25 μm) (eluent: cyclohexane/ethyl acetate, 90/10),4.62 g of13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydroxazol-5-yl]carbonyl-7-O-triethylsilylbaccatinIII were obtained in the crystalline state (Yd=97%).

[0238] The compound thus obtained exhibited the followingcharacteristics:

[0239] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.23 (2H, d, J=7.2 Hz), 8.07 (2H,d, J=7.3 Hz), 7.63 (1H, t, J=7.4 Hz), 7.58 (1H, t, J=7.4Hz), 7.49 (4H,m), 7.38(5H, m), 6.42 ((1H, s), 6.18 (1H, t, J=8.2 Hz), 5.68 (1H, d,J=7.1Hz), 5.60 (1H, d, J=6.5 Hz), 4.95 (2H, d), 4.50 (1H, dd, J=10.5 and6.7 Hz), 4.29 (1H, d, J=8.4 Hz), 4.14 (1H, d, J=8.4 Hz), 3.83 (1H, d,J=7.1Hz), 2.55 (1H, m), 2.37 (1H, dd, J=15.3 and 9.3 Hz), 2.26 (1H, dd,J=15.3 and 8.6 Hz), 2.16 (3H, s),2.07 (3H, s), 1.99 (3H, s), 1.89 (1H,m), 1.72 (1H, s), 1.69 (3H, s), 1.23 (3H, s), 1.19 (3H, s), 0.92 (9H, t,J=8 Hz), 0.57 (6H, m).

Example 2413-O-[[(4S,5R)-2,4-Diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-phenoxyacetylbaccatinIII

[0240]

[0241] 380 mg (1.84 mmol) of dicyclohexylcarbodiimide were added to astirred solution, at room temperature and under an inert atmosphere, of490 mg (1.83 mmol) of (4S,5R)-2,4-diphenyl4,5-dihydrooxazol-5-carboxylicacid in 10 mL of anhydrous toluene. After stirring for 5 min, 660 mg(0.92 mmol) of 7-O-phenoxyacetylbaccatin III and 112 mg (0.92 mmol) of4-dimethylaminopyridine were added and the reaction mixture was broughtto 70° C. for 2 h. After returning to room temperature and removing theinsoluble materials by filtration, the organic phase was concentratedunder reduced pressure. After purifying the crude product by silica gelchromatography (15-40 μm) (eluent: cyclohexanelethyl acetate, 99/1), 800mg of13-O-[[4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-phenoxyacetylbaccatinIII were obtained in the crystalline state (Yd=90%).

[0242] The compound thus obtained exhibited the followingcharacteristics:

[0243] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.18 (2H, d, J=7 Hz), 8.07 (2H,d, J=7.3 Hz), 7.63 (1H, t, J=7.4 Hz), 7.59-7.32 (1 OH, m), 7.28 (2H, t,J=7.5 Hz), 6.94 (3H, m), 6.23 (1H, s) and (1H, m), 5.70 (1H, dd, J=10.4and 7.1Hz), 5.67 (1H, d, J=7.3 Hz), 5.58 (1H, d, J=7 Hz), 4.93 (2H, d),4.79 and 4.53 (2H, 2d, J=15.9 Hz), 4.30 and 4.13 (2H, 2d, J=8.5Hz), 3.97(1H, d, J=6.9Hz), 2.67 (1H, m), 2.38 (1H, dd, J=15.2 and 9.3 Hz), 2.26(1H, dd, J=15.2 and 8.4 Hz), 2.15 (3H, s), 2.02 (3H, s), 1.95 (3H, s)and (1H, m), 1.80 (3H, s), 1.74 (1H, s), 1.25 (3H, s), 1.17 (3H, s).

Example 2513-O-[[(4S,5R)-2,4-Diphenyl4,5-dihydrooxazol-5-yl]carbonyl]-7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatinIII

[0244]

[0245] 27 mg (0.13 mmol) of dicyclohexylcarbodiimide were added to astirred solution, at room temperature and under an inert atmosphere, of35 mg of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic acid in 3mL of anhydrous toluene. After stirring for 5 min, 51 mg (0.065 mmol) of7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatin III and 8 mg (0.065 mmol)of 4-dimethylaminopyridine were added and the mixture was brought to 70°C. for 1 h. After returning to room temperature and removing theinsoluble materials by filtration, the organic phase was concentratedunder reduced pressure and the residue obtained was purified by silicagel chromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 9/1).

[0246] 0.99 g of the compound cited in the title was thus obtained inthe form of a white solid (Yd=67%) which exhibited the followingcharacteristics:

[0247] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.18 (2H, d, J=7.2 Hz), 8.07 (2H,d, J=7.3 Hz), 7.65 (1H, t, J=7.4 Hz), 7.59 (1H, t, J=7.3 Hz), 7.52 (4H,m), 7.39 (5H, m), 6.35 (1H, s), 6.24 (1H, t, J=8.4 Hz), 5.68 (1H, d,J=7.1Hz), 5.59 (1H, d, J=7 Hz) and (1H, dd), 4.95 (1H, d), 4.94 (1H, d,J=7 Hz), 4.31 and 4.15 (2H, 2d, J=8.4 Hz), 3.97 (1H, d, J=6.9 Hz), 2.64(1H, m), 2.37 (1H, dd, J=15.1 and 6 Hz), 2.27 (1H, dd, J=15.2 and 8.5Hz), 2.16 (3H, s), 2.01 (3H, s), 1.98 (3H, s), 1.83 (3H, s), 1.72 (1H,s), 1.25 (3H, s), 1.18 (3H, s).

Example 2613-O-[[(4S,5R)-2,4-Diphenyl-4,5dihydrooxazol-5-yl]carbonyl]-7,10-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-10-deacetylbaccatinIII

[0248]

[0249] 7 mg (0.06 mmol) of dicyclohexylcarbodiimide were added to astirred solution, at room temperature and under an inert atmosphere, of4 mg (0.015 mmol) of (4S,5R)-2,4-diphenyl4,5-dihydrooxazol-5-carboxylicacid in 0.5 mL of anhydrous toluene. After stirring for 5 min, asolution of 5 mg (0.0065 mmol) of7,10-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-10-deacetylbaccatinIII and of 1 mg (0.0078 mmol) of 4-dimethylaminopyridine in 1 mL ofanhydrous toluene was added. After stirring for 20 min at roomtemperature, the mixture was brought to 50° C. for an additional 20 min.After returning to room temperature, the organic phase was diluted with5 mL of dichloromethane, washed with 2 mL of a saturated aqueous sodiumchloride solution, dried over MgSO₄ and concentrated under reducedpressure. After purifying the crude product by silica gel chromatography(15-25 μm) (eluent: cyclohexane/ethyl acetate, 7/3), 6 mg of thederivative cited in the title were obtained (Yd=90%) in the amorphousstate.

[0250] The compound obtained exhibited the following characteristics:

[0251] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.21 (2H, d, J=7.2 Hz), 8.07 (2H,d, J=7.6 Hz), 7.63 (1H, t, J=7.5 Hz), 7.59 (1H, t, J=7.4 Hz), 7.50 (2H,t, J=7.4 Hz), 7.39 (5H, m), 6.26 (1H, t), 5.64 (1H, d, J=7 Hz), 5.59(1H, d, J=6.9 Hz), 5.54 (1H, s), 4.93 (1H, d, J=6.8 Hz) and (1H, m),4.68 (1H, dd), 4.28 and 4.16 (2H, 2d, J=8 Hz), 3.84 (1H, d, J=7.3 Hz),2.48 (1H, m), 2.35 and 2.25 (2H, 2dd), 2.02 (3H, s), 1.88 (3H, s) and(1H, m), 1.67 (3H, s), 1.63 (1H, s), 1.30 to 0.90 (34H, m).

Example 2713-O-[[(4S,5R)-3-N-Benzoyl-4-phenyloxazolidin-3one-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII

[0252]

[0253] 28 mg (0.136 mmol) of dicyclohexylcarbodiimide were added to astirred solution at room temperature under an inert atmosphere of 40 mg(0.137 mmol) of(4S,5R)-3-N-benzoyl-4-phenyloxazolidin-3-one-5-carboxylic acid in 2 mLof anhydrous toluene. After stirring for 5 min, 30 mg (0.043 mmol) of7-O-triethylsilylbaccatin III and 8 mg (0.066 mmol) of4-dimethylaminopyridine were added and the reaction mixture was broughtto 60° C. for 13 h. After returning to room temperature, the reactionmixture was diluted with 10 mL of dichloromethane and the organic phasewas washed with 5 mL of a saturated sodium chloride solution, dried overMgSO₄ and concentrated under reduced pressure. After purifying by silicagel chromatography (15-14 μm) (eluent: cyclohexane/ethyl acetate, 2/1),13 mg of the derivative cited in the title were obtained in theamorphous state (Yd=31%).

[0254] The compound obtained exhibited the following characteristics:

[0255] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.06 (2H, d, J=7.3 Hz), 7.72 (2H,d, J=7 Hz), 7.63 (1H, t, J=7.4 Hz), 7.58 (1H, t, J=7.4 Hz), 7.54 to 7.44(8H, m), 7.40 (1H, t), 6.44 (1H, s), 6.33 (1H, t), 5.73 (1H, d, J=5.7Hz), 5.67 (1H, d, J=5.7 Hz), 4.96 (1H, d, J=5.8 Hz), 4.88 (1H, d, J=8.3Hz), 4.45 (1H, dd, J=10.4 and 6.6 Hz), 4.27 and 4.12 (2H, 2d, J=8.3 Hz),3.80(1H, d, J=7 Hz), 2.50(1H, m), 2.26 (2H, m), 2.19(3H, s), 2.07 (3H,s), 1.98 (3H, s), 1.85 (1H, m), 1.76 (1H, s), 1.67 (3H, s), 1.24 (3H,s), 1.23 (3H, s), 0.91 (9H, t, J=7.9 Hz), 0.56 (6H, m).

Example 2813-O-[[(4S,5R)-4-Phenyloxazolidin-3-one-5-yl]carbonyl]-7,10-O-di(phenoxyacetyl)-10-deacetylbaccatinIII

[0256]

[0257] 65 mg (0.315 mmol) of dicyclohexylcarbodiimide were added to astirred solution, at room temperature and under an inert atmosphere, of78 mg (0.293 mmol) of(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-carboxylic acid in 3 mL ofanhydrous toluene. After stirring for 5 min, a solution of 237 mg (0.293mmol) of 7,10-O-bis(phenoxyacetyl)-10-deacetylbaccatin III and 36 mg(0.295 mmol) of 4-dimethylaminopyridine in 3 mL of toluene was added andthe reaction mixture was brought to 60° C. for 1 h. After returning toroom temperature and removing the insoluble materials by filtration, theorganic phase was concentrated under reduced pressure and the crudeproduct obtained was purified by silica gel chromatography (15-40 μm)(eluent: cyclohexane/ethyl acetate, 1/1).

[0258] 280 mg of the compound cited in the title were thus obtained inthe amorphous state (Yd=90%), which compound exhibited the followingcharacteristics:

[0259] 400 MHz ¹H NMR (CDCl₃) (δ ppm): 8.18 (2H, d, J=7 Hz), 8.06 (2H,d, J=7.1Hz), 7.64 (1H, t, J=7.4Hz), 7.58 (1H, t, J=7.3 Hz), 7.51 (4H,m), 7.39 (5H, m), 7.25 (4H, m), 6.96 (4H, m), 6.85 (2H, d, J=8 Hz), 6.33(1H, s), 6.19 (1H, t, J=9 Hz), 5.68 (1H, dd, J=10.5 and 7.1Hz), 5.65(1H, d, J=6.9 Hz), 5.59 (1H, d, J=7 Hz), 4.93 (2H, d, J=7.1Hz), 4.79(2H, s), 4.63 and 4.40 (2H, 2d, J=15.9 Hz), 4.30 and 4.13 (2H, 2d,J=8.4Hz), 3.94 (1H, d, J=6.9Hz), 2.68 (1H, m), 2.37 (1H, dd, J=15.3 and9.3Hz), 2.24 (1H, dd, J=15.3 and 8.7 Hz), 2.02 (3H, s), 1.95 (3H, s),1.80 (3H, s) and (1H, m), 1.69 (1H, s), 1.12 (3H, s), 1.01 (3H, s).

IlI. Hemisynthesis Example 29 Preparation of Paclitaxel a) From13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII

[0260] 0.6 L (0.6 mol) of a 1M aqueous HCl solution was added to astirred solution, at room temperature and under an inert atmosphere, of90 g (0.095 mol) of 13-O-[[(4S,5R)-2,4-diphenyl4,5-dihydrooxazol-5-yl]carbonyl]-7-O-triethylsilylbaccatinIII in a mixture of tetrahydrofuran (1.2 L) and methanol (1.2 L) and thereaction mixture was stirred at room temperature for 4 h 30. Afteradding 3.5 L of a saturated aqueous sodium hydrogencarbonate solution,the solution was kept homogeneous by addition of 6 L of tetrahydrofuranand 6 L of water and the reaction mixture was stirred for an additional1 h 30. After adding 15 L of ethyl acetate and 15 L of osmosed water,the residual aqueous phase was extracted with ethyl acetate (15 L). Theorganic phase was dried over MgSO₄ and concentrated under reducedpressure and the crude product thus obtained was purified by silica gelchromatography (15-40 μm) (eluent: cyclohexane/ethyl acetate, 1/1).

[0261] 75 g of taxol were thus isolated in the crystalline state(Yd=95%), the characteristics of which were in every respect inaccordance with the literature data.

b) From13-O-[[(4S,5R)-2,4-diphenyl4,5-dihydrooxazol-5-yl]carbonyl]-7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatinIII

[0262] 90 μL (0.09 mmol) of a 1M aqueous HCl solution were added to astirred solution, at room temperature and under an inert atmosphere, of15 mg (0.0148 mmol) of 13-O-[[(4S,5R)-2,4-diphenyl-4,5-dihydrooxazol-5-yl]carbonyl]-7-O-(2,2,2-trichloro-t-butoxycarbonyl)baccatinIII in a mixture of tetrahydrofuran (0.18 mL) and methanol (0.18 mL) andthe reaction mixture was stirred at room temperature for 8 h. Afteradding 0.6 mL of a saturated aqueous sodium hydrogencarbonate solution,the solution was kept homogeneous by addition of 1 mL of tetrahydrofuranand 1 mL of water and the reaction mixture was stirred for an additional1 h 30. After adding 2.5 mL of ethyl acetate and 2.5 mL of osmosedwater, the residual aqueous phase was extracted with ethyl acetate (2.5mL). The combined organic phases are dried over MgSO₄ and concentratedunder reduced pressure.

[0263] 14 mg of 7-O-(2,2,2-trichloro-t-butoxycarbonyl)taxol are thusobtained in the crude state (Yd=93%), which product was used withoutadditional purification in the following stage.

[0264] 30 μL (0.525 mmol) of acetic acid and 22.5 mg (0.344 mmol) ofzinc powder were added to a stirred solution at room temperature of 13mg (0.0128 mmol) of 7-O-(2,2,2-trichloro-t-butoxycarbonyl)taxol in 2 mLof ethyl acetate. After stirring for 2 h 30 at room temperature andmonitoring by T.L.C., and after diluting the reaction mixture with 3 mLof ethyl acetate, the organic phase was washed with osmosed water (1mL), with a saturated aqueous sodium hydrogencarbonate solution (1 mL)and again with water, dried over MgSO₄ and concentrated under reducedpressure.

[0265] After chromatographing the crude product on silica gel (15-40 μm)(eluent: cyclohexane/ethyl acetate, 6/4), 9.5 mg of taxol were thusisolated in the crystalline state (Yd=89%).

1. Process for the preparation of taxane side chain precursors in whicha cis-β-arylglycidate derivative of general formula I

in which Ar represents an aryl radical and R represents a hydrocarbonradical, preferably a linear or branched alkyl or a cycloalkyloptionally substituted by one or more alkyl groups, is converted, so asto regio- and stereospecifically introduce the β-N-alkylamide and theα-hydroxyl or their cyclic precursors in a single stage by a Ritterreaction, which consists either: a of the direct synthesis of a linearchain by reacting a cis-β-arylglycidate derivative of general formula Idefined above with a nitrile of formula R₂—CN in which R2 represents anaryl radical, in the presence of a protonic acid and of water, in orderto obtain a β-arylisoserine derivative of general formula IIa,

in which Ar, R and R₂ are defined above; or b of the direct synthesis ofa cyclic chain by reacting a cis-β-arylglycidate derivative of generalformula I defined above with a nitrile of formula R′₂—CN in which R′₂represents R₂ defined above or a lower alkyl or lower perhaloalkylradical, such as trichloromethyl, in the presence of a Lewis acid or ofa protonic acid, in anhydrous medium, in order to obtain the oxazolineof general formula IIb

in which Ar, R and R′₂ are defined above.
 2. Process according to claim1, characterized in that R represents an optically pure enantiomer of ahighly sterically hindered chiral hydrocarbon radical, advantageously acycloalkyl substituted by one or more alkyl groups, in particular acyclohexyl.
 3. Process according to claim 2, characterized in that R isone of the enantiomers of the menthyl radical, in particular(+)-menthyl.
 4. Process according to one of claims 1 to 3, characterizedin that the cis-β-phenylglycidate derivative of general formula I is of(2R,3R) configuration and the derivatives of general formulae IIa andIIb obtained are of (2R,3S) configuration.
 5. Process according to oneof claims 1 to 4, characterized in that Ar and R₂ represent a phenyl. 6.Process according to one of claims 1 to 5, characterized in that theprotonic acid in the stage a is chosen from sulphuric acid, perchloricacid or tetrafluoroboric acid, the Lewis acid in the stage b is chosenfrom the boron trifluoride acetic acid complex, boron trifluorideetherate, antimony pentachloride, tin tetrachloride or titaniumtetrachloride and the protonic acid in the stage b is tetrafluoroboricacid.
 7. Process according to one of claims 1 to 6, characterized inthat the β-arylisoserine derivative of general formula IIa is convertedby protection of the hydroxyl by an appropriate protective group (GP),in order to obtain a derivative of general formula II′a

in which Ar, R and R₂ are defined above and GP represents a protectivegroup for the hydroxyl functional group which is appropriate for thesynthesis of taxanes, in particular chosen from alkoxy ether, aralkoxyether, aryloxy ether or haloalkoxycarbonyl radicals, such as, forexample, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl or(β-trimethyl-silylethoxy)methyl groups, tetrahydropyranyl orβ-alkoxycarbonyl radicals, β-halogenated or alkylsilyl ethers, oralkoxyacetyl, aryloxyacetyl, haloacetyl or formyl radicals.
 8. Processaccording to one of claims 1 to 6, characterized in that theβ-arylisoserine derivative of general formula IIa is converted intonovel oxazolidinone cyclic intermediates of general formula IIIa

in which Ar and R are defined above by reacting a β-arylisoserinederivative of general formula IIa according to one of claims 1 to 5 witha haloalkoxycarbonyl ester, in particular 2,2,2-trichloroethoxycarbonyl(TrOC), and then by cyclization in the presence of a strong organicbase, such as diazabicycloundecene (DBU), optionally convertedsubsequently into the corresponding amide of general formula III′a

in which Ar and R are defined above and R″₂ represents R′₂ definedabove, an alkoxy radical or a linear or branched alkyl radicalcomprising at least one unsaturation.
 9. Process according to one ofclaims 1 to 6, characterized in that the oxazoline of general formulaIIb is hydrolysed in acidic medium in order to obtain theβ-arylisoserine derivative of general formula IIIb,

in which Ar, R and R′₂ are defined above, optionally convertedsubsequently into the corresponding amide of general formula III′b

in which Ar, R, R′₂ and R″₂ are defined above.
 10. Process according toone of claims 1 to 9, characterized in that the cis-β-arylglycidatederivative of general formula I

in which Ar is defined above and R represents an optically pureenantiomer of a highly sterically hindered chiral hydrocarbon radical,is prepared by reacting the aldehyde of formula Ar—CHO with thehaloacetate of formula X—CH₂—COOR Ar and R being defined above and Xrepresenting a halogen, in particular a chlorine or a bromine. 11.Process according to one of claims 1 to 10, characterized in that thederivatives of formulae IIa, II′a, IIb, IIIa, III′a, IIIb and III′bdefined above in which R represents a hydrogen atom are obtained bycontrolled saponification.
 12. Precursor compounds of taxane sidechains, characterized in that they are selected from the derivatives offollowing general formulae I, IIa, IIb, II′a, IIIb and III′b:

in which Ar, R₂, R′₂, R″₂ and GP are defined in one of claims 1 to 3 and5, and R represents an optically pure enantiomer of a highly stericallyhindered chiral hydrocarbon radical.
 13. Compounds according to claim12, characterized in that R is one of the enantiomers of the menthylradical, in particular (+)-menthyl.
 14. Compounds according to either ofclaims 12 and 13, characterized in that the cis-β-phenylglycidatederivative of general formula I is of (2R,3R) configuration and thederivatives of general formulae IIa, IIb, IIIb and III′b are of (2R,3S)configuration.
 15. Precursor compounds of taxane side chains,characterized in that they are selected from the derivatives offollowing general formulae IIIa and III′a:

in which Ar, R and R′₂ are defined above or R represents a hydrogenatom.
 16. Compounds according to claim 15, characterized in that theyare of (2R,3S) configuration.
 17. Process for the preparation of taxanesof general formula IV, C—B  IV in which B represents a radical ofgeneral formula V

in which Ac represents the acetyl radical, Bz represents the benzylradical, Me represents the methyl radical, R₄ represents an acetylradical or a protective group for the hydroxyl functional group GP1, andR₅ represents a protective group for the hydroxyl functional group GP2,and C represents a side chain chosen from the radicals of followingformulae IIa, II′a, IIb, IIIa, III′a, IIIb and III′b:

in which Ar, R₂, R′₂, R″₂ and GP are defined above, by esterification ofan appropriate baccatin III derivative of general formula V, carrying aC-13 hydroxyl functional group, with one of the derivatives of formulaeIIa, II′a, IIb, IIIa, III′a, IIIb and III′b, for which R represents ahydrogen atom, obtained by the process according to claim
 11. 18.Process according to claim 17, characterized in that the GP1 and GP2protective groups are, independently of one another, conventional groupsemployed in the hemisynthesis of taxanes, such as trialkylsilyls orTROC, or linear or branched bulky haloalkoxycarbonyl radicals comprisingat least one halogen atom, acyl radicals in which the carbon α to thecarbonyl functional group carries at least one oxygen atom, or atrialkylgermanyl radical or GP1 and GP2 together form a divalent radicalof formula —SiR₇—O—SiR₈— in which R₇ and R₈, independently of oneanother, represent a sterically hindered alkyl radical.
 19. Processaccording to either of claims 17 and 18, characterized in that the acylradicals in which the carbon a to the carbonyl functional group carriesat least one oxygen atom are chosen from alkoxy- or aryloxyacetylradicals of formula R₆—O—CH₂—CO— in which R₆ represents a stericallyhindered alkyl radical, a cycloalkyl radical or an aryl radical, orarylidenedioxyacetyl radicals of formula

in which Ar″ represents an arylidene radical.
 20. Process according toclaim 19, characterized in that: the sterically hindered alkyl radicalis a linear or branched C₁-C₆ alkyl radical substituted by one or morebulky substituents chosen from halogens or linear or branched C₁-C₆alkyl, linear or branched C₁-C₆ alkoxy or C₃-C₆ cycloalkyl or arylradicals, the cycloalkyl radical is a C₃-C₆ cycloalkyl radicaloptionally substituted by one or more bulky substituents chosen fromhalogens or linear or branched C₁-C₆ alkyl, linear or branched C₁-C₆alkoxy or aryl radicals, preferably a cyclohexyl radical substituted byone or more linear or branched C₁-C₆ alkyl radicals, for examplementhyl, its racemate or its enantiomers and their mixtures in allproportions, the aryl radical is a phenyl, naphthyl, anthryl orphenantryl radical optionally substituted by one or more bulkysubstituents chosen from halogens or linear or branched C₁-C₆ alkyl,linear or branched C₁-C₆ alkoxy or aryl radicals, in particular thephenyl radical, preferably a phenyl radical optionally substituted byone or two above bulky substituents ortho- and ortho′- to the etherbond, and the arylidene radical is a phenylene, naphthylene, anthryleneor phenanthrylene radical optionally substituted by one or more bulkysubstituents chosen from halogens or linear or branched C₁-C₆ alkyl,linear or branched C₁-C₆ alkoxy or aryl radicals, in particular thephenyl radical.
 21. Process according to either of claims 17 and 18,characterized in that R₄ represents an acetyl radical and GP2 representsa trialkylsilyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2,2,2,1-tetrachloroethoxycarbonyl,2,2,2-trichloro-t-butoxycarbonyl, trichloromethoxycarbonyl,phenoxyacetyl or trialkylgermanyl radical.
 22. Process according toeither of claims 17 and 18, characterized in that R₄ represents a GP1group and GP1 and GP2 represent a 2,2,2-trichloroethoxy-carbonyl orphenoxyacetyl radical or together form a divalent radical of formula—SiR₇—O—SiR₈—in which R₇ and R₈ each represent an isopropyl radical. 23.Process according to one of claims 17 to 21, characterized in that Crepresents a radical of formula IIa with Ar and R₂ representing a phenyland R4 represents an acetyl radical.
 24. Process according to one ofclaims 17 to 23, characterized in that, subsequently, the hydroxyls ofthe derivatives of general formula IV are deprotected and, ifappropriate, simultaneously or separately, the oxazoline ring of theradicals of formula IIb or IIIa is opened, in order to produce a taxanederivative of general formula VI

in which Ac, Bz, Me and R′₂ are defined in one of the preceding claims,R₄ represents a hydrogen atom or an acetyl radical, and R₅ represents ahydrogen atom.
 25. Taxane derivatives of general formula IV C—B  IV inwhich C and B are defined in one of claims 17 to 23, with the exceptionof the derivatives in which C represents a radical of formula IIa, II′a,IIb, IIIb or III′b, and GP1 and/or GP2 are, independently of oneanother, conventional groups employed in the hemisynthesis of taxanes,such as trialkylsilyls or TrOC.
 26. Baccatin III derivatives which areof use in the hemisynthesis of taxanes, characterized in that they arechosen from the derivatives of general formula V

in which Ac represents the acetyl radical, Bz represents the benzylradical, Me represents the methyl radical, R₄ represents an acetylradical or a protective group for the hydroxyl functional group GP1, R₅represents a protective group for the hydroxyl functional group GP2, andGP1 and GP2 are, independently of one another, bulky haloalkoxycarbonylradicals, with the exception of TrOC, acyl radicals in which the carbonα to the carbonyl functional group carries at least one oxygen atom, ortrialkylgermanyl radicals or GP1 and GP2 together form a divalentradical of formula —SiR₇—O—SiR₈— in which R₇ and R₈, independently ofone another, represent a sterically hindered alkyl radical.